Study On The Synthetic Methods Of Antiplatelet Drug Elinogrel

Thromboembolic diseases,with high rate of morbidity and disability,are one of the major diseases seriously threatening to human health.Despite the widespread use of antithrombotic drugs to prevent and treat the thrombosis,thromboembolic diseases continue to be the major cause of death in the world.Governments have regarded the development of antithrombotic drugs as a primary task.Along with the development of molecular biology,people have a better understanding of the mechanism of thrombus formation,which lays a solid foundation to look for novel antithrombotic drugs.Platelets play a critical role in the pathogenesis of thrombosis.As a result of the injury of the vascular endothelial cells,the subendothelium is exposed,which leads to platelet adhesion activation and aggregation.Blood platelets activation is determined by a variety of receptor-mediated signaling pathways through the corresponding agonists.As an important platelet receptor agonist,adenosine diphosphate(ADP)has two types of receptors on the surface of blood platelets:P2Y1 receptor and P2Y12 receptor.Both of them are G protein-coupled receptors.P2Y1 receptor is coupled with a Gq protein,and P2Y12 receptor is linked to a Gi protein.ADP,through its P2Y1 receptor,is able to induce platelets shape change,calcium mobilization,and rapidly reversible platelet aggregation.Through its P2Y12 receptor,ADP can inhibit adenylate cyclase to reduce the cyclic adenosine monophosphate(cAMP)and promote the platelet aggregation.Platelets activation is adjusted by P2Y1 and P2Y12 receptors.Both of them are indispensable.P2Y12 is mostly found in the platelet plasma membrane.It means that P2Y12 receptor antagonist mainly act on platelets,and therefore P2Y12 antagonists,as antithrombotic drugs with fewer side effects,become the research focus at home and abroad.Elinogrel is developed by Novartis and Portola Pharmaceuticals,as a novel direct-acting,potent and reversible P2Y12 antagonist.It mimics chemical structure of ATP and can be administered orally or intravenously.Phase II trials of Elinogrel demonstrated that it had advantages over Clopidogrel,including less variable,more rapid,and more complete inhibition of platelet function without an unacceptable increase of bleeding.Elinogrel has a bright development prospect.Phase III trials of Elinogrel are still pending to be designed.Objective:To synthesize P2Y12 antagonist Elinogrel and its potassium salt,and to optimize the synthetic conditions.Methods:The 2-amino-4,5-difluorobenzoic acid methyl ester(7)was obtained from 3,4-difluorobenzoic acid by nitration,esterification and reduction.The intermediate(4-aminophenyl)carbamic acid 1,1-dimethylethyl ester(10)was prepared through protection of 4-nitroaniline(8)with di-tert-butyl dicarbonate,followed by catalystic hydrogenation with 10%Pd/C.The reaction of 2-isocyanato-4,5-difluorobenzoic acid methyl ester(11),prepared from intermediate 7 and bis(trichloromethyl)carbonate(BTC)in dry 1,2-dichloroethane,with compound 10 gave the desired product 2-[N'-[4-[(tert-butoxycarbonyl)-amino]phenyl]ureido]-4,5-difluorobenzoic acid methyl ester(12).Compound 12 was treated with sodium methoxide to produce N-[4-(6,7-difluoro-1,4-dihydro-2,4-dioxo-3(2H)-quinazolinyl)phenyl]carba-mic acid 1,1-dimethylethyl ester(13),and then the 3-(4-aminophenyl)-6,7-difluo-roquinazoline-2,4(1H,3H)-dione hydrochloride(14)was obtained by deprotection of N-Boc with 2N HC1/C2H5OH.The C-7 fluoro of compound 14 was then displaced by treatment with methylamine in DMSO at about 110? to afford 3-(4-aminophenyl)-6-fluoro-7-(methylamino)-2,4(1H,3H)-quinazolinedione(15).Chlorothiophene(16)was chlorosulfonated and treated with ammonium hydroxide to give 5-chloro-2-thiophene sulfonamide(18).The key intermediate[(5-chlorothiophen-2-yl)sulfonyl]carbamic acid ethyl ester(19)was generated from the reaction between 18 and ethyl chloroformate.The preparation of target sulfonylurea 2 could be accomplished by the reaction of 15 and 19.Finally 5-chloro-N-[[[4-[6-fluoro-1,4-dihydro-7-(methylamino)-2,4-dioxo-3(2H)-quinazolinyl]phenyl]a mino]-carbonyl]-2-thiophenesulfonamide potassium salt(1)was obtained from the reaction between 2 and potassium hydroxide solution.The contents of Elinogrel(2)and its potassium salt(1)were measured by High Performance Liquid Chromatography(HPLC).Results:Elinogrel and it's potassium salt have been synthesized according to the process we designed,and were confirmed by 1H-NMR and MS-ESI(m/z).Some of the synthetic conditions were optimized.Elinogrel:white solid,mp.>300?,purity:99.36%Elinogrel potassium salt:white solid,mp.250?(decomposition),purity:99.88%Conclusion:Elinogrel and its potassium salt were synthesized.Some of the reaction conditions were optimized.The starting materials was inexpensive and easy to obtain.The reaction conditions were mild,and the work-up processing was simple.